SAFETY AND FEASIBILITY OF IRRADIATION AND NIVOLUMAB IN ESOPHAGEAL CANCER (INEC-STUDY) – A PHASE I/II TRIAL
- Conditions
- Eosophageal cancer
- Interventions
- Registration Number
- 2023-510124-77-01
- Lead Sponsor
- Oslo University Hospital HF
- Brief Summary
Safety measurements done to determine the safety profile of the treatment; safety parameters included adverse events, biochemistry, hematology, vital signs and performance status.
Adverse events are recorded according to CTCAE v5.0 (CTCAE grade 2-5 rate)
- Detailed Description
Three parallel cohort, multicenter, open-label, phase I/II clinical trial to analyze the safety and feasibility of PD-1 inhibition with Nivolumab given concomitantly with standard radiotherapy regimens in the treatment of esophageal cancer.
Cohort A: Advanced/inoperable esophageal cancer, eligible for palliative radiotherapy of the primary tumor.
Cohort B: Inoperable esophageal cancer without metastases, eligible for definitive chemoradiotherapy Cohort C: Operable esophageal cancer eligible for neoadjuvant chemoradiotherapy
Recruitment & Eligibility
- Status
- Authorised, recruitment pending
- Sex
- Not specified
- Target Recruitment
- 30
Age > 18 years
Specific inclusion criteria - Cohort A: 1. Eligible for palliative fractionated radiotherapy of the esophageal- or gastroesophageal cancer as determined by the multidisciplinary team (MDT) meeting. 2. Expected survival >3 months. 3. Not bulky disease, i.e. palliative radiotherapy towards the primary tumor is intended to palliate dysphagia and/or pain and systemic treatment could be delayed to AFTER protocol therapy if possible.
Specific inclusion criteria – Cohort B: 1. Eligible for definitive chemoradiation of localized but inoperable esophageal- or gastroesophageal cancer as determined by the multidisciplinary team (MDT) meeting. 2. Regional disease, i.e. no metastasis outside the radiation field (PTV). 3. Considered candidate/ able to adhere to the intended chemoradiotherapy
Specific inclusion criteria – Cohort C: 1. Eligible for neoadjuvant chemoradiotherapy and surgery of the esophageal- or gastroesophageal cancer as determined by the multidisciplinary team (MDT) meeting. 2. Regional disease, i.e. no metastasis outside the radiation field (PTV). 3. Considered candidate and able to adhere to the intended neoadjuvant chemoradiotherapy and planned surgery.
Patients should have previously untreated histologically proven squamous cell carcinoma or adenocarcinoma of the esophagus or the gastroesophageal junction (GEJ), Siewert I, II or III
Must be ambulatory with a performance status ECOG 0 or 1
Adequate organ function based on clinical examiniation and lab values as defined in the below: Absolute neutrophil count: ≥ 1,5 x109/L Platelets: ≥ 100 x109/L Hemoglobin: ≥ 9 x109/L Creatinine ≤ 1,5 upper limit normal (ULN) OR measured/calculaterd GFR≥60 mL/min Albumin ≥ 30 g/L Total bilirubin ≤ 1,5 ULN ASAT and ALAT ≤ 2,5 ULN, or ≤ 5 ULN for subjects with liver mets. International Normalized Ratio (INR) ≤ 1,5 ULN and Activated Partial Thromboplastin Time (TT) ≤ 1,5 ULN unless subject is receiving anticoagulant therapy. Such therapy (if indicated) should be converted to adequate therapy with low-molecular weight heparin such as Dalteparin before chemotherapy or treatment with IMP.
Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 28 days prior to the start of study drug (screening phase). Women must not be breastfeeding.
WOCBP should use highly effective adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for Nivolumab to undergo five half-lives) after the last dose of investigational drug. Adequate methods are described in Appendix I.
Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception during the study treatment period and until 7 months after last dose of Nivolumab
Signed informed consent and expected cooperation of the patients for the treatment and follow up must be obtained and documented according to ICH GCP, and national/local regulations.
If Dysphagia score >2, a nasogastric feeding tube should be inserted during the aid of gastroscopy, and nasogastric tube feeding started before radiotherapy.
Previous treatment with radiotherapy towards volumes within the thoracic cavity
History of prior malignancy within the last 5 years, excluding curatively treated basal cell or squamous cell carcinoma of the skin.
Known history of brain metastases
Need to use immunosuppressive drugs including, but not limited to: Glukocorticoids, everolimus, sirolimus, disease-modifying anti-rheumatic drugs (DMARDS)
Positive pregnancy test (positive hCG blood test)
Known allergy, hypersensitivity, or contraindication to the investigational product Nivolumab, or the drugs paclitaxel and docetaxel used in the standard chemoradiotherapy protocols (Cohorts B and C) or any components used in their preparation or has a contraindication to taxane therapy.
Any reason why, in the opinion of the investigator, the patient should not participate.
Previous treatment with any PD-1 or PD-L1/2 inhibitor
Hypersensitivity to the investigational product or any of the drug formula contents
Esophageal stenting
T4b if infiltration into the aorta or the trachea
History of prior autoimmune disorders requiring systemic therapy (excluding Insulin or Thyroid replacement therapy)
History of HIV 1 /2, Hepatitis B or C infection
History of Immunodeficiency disorders (i.e. immunoglobulin deficiency or white blood cell lineage depletion disorders)
Participation in any other interventional clinical trial with an investigational product
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Cohort A Radiotherapy Subjects having palliative radiotherapy towards esophageal tumor will receive concomitant therapy With Nivolumab i.v. 240mg Q2W: first 6 patients, 360mg Q3W: Next 6 patients or 480mg Q4W: Last 6 patients, treatment to progression or up to 2 years of treatment. Radiotherapy: 2 Gy / day, (5 fx/week) to a total of 20 - 50 Gy in 25fx (2-4Gy/fx) at the decision of the responsible physician. Cohort B Radiotherapy Subjects receiving definitive chemoradiotherapy for esophageal cancer will receive concomitant therapy with Nivolumab 240mg Q2W, during RT, and continued with 480mg Q4W, treatment to progression or up to 1 year after completion of radiotherapy. 6 patients in total. Chemotherapy: Paclitaxel i.v. 175mg/m2 and Carboplatin AUC5, then after 21 days Radiotherapy 1,8 Gy / day (5 fx/week) up to 50,4 Gy in 28fx and concomitantly Paclitaxel 50mg/m2 and Carboplatin AUC2 Q1W and Nivolumab as described above. Cohort B Chemotherapy Subjects receiving definitive chemoradiotherapy for esophageal cancer will receive concomitant therapy with Nivolumab 240mg Q2W, during RT, and continued with 480mg Q4W, treatment to progression or up to 1 year after completion of radiotherapy. 6 patients in total. Chemotherapy: Paclitaxel i.v. 175mg/m2 and Carboplatin AUC5, then after 21 days Radiotherapy 1,8 Gy / day (5 fx/week) up to 50,4 Gy in 28fx and concomitantly Paclitaxel 50mg/m2 and Carboplatin AUC2 Q1W and Nivolumab as described above. Cohort C Radiotherapy Subjects with operable esophageal cancer eligible for neoadjuvant chemoradiotherapy will receive Nivolumab 240mg Q2W, concomitantly with RT Then surgery 4-12 weeks after RT. Within 6-12 months after surgery: Adjuvant Nivolumab 480mg Q4W, for 12 months. 6 patients in total. Neoadjuvant chemotherapy: Concomitantly Paclitaxel 50mg/m2 and Carboplatin AUC2 Q1W and Radiotherapy: 41,4 Gy in 23 fractions. Cohort C Surgery Subjects with operable esophageal cancer eligible for neoadjuvant chemoradiotherapy will receive Nivolumab 240mg Q2W, concomitantly with RT Then surgery 4-12 weeks after RT. Within 6-12 months after surgery: Adjuvant Nivolumab 480mg Q4W, for 12 months. 6 patients in total. Neoadjuvant chemotherapy: Concomitantly Paclitaxel 50mg/m2 and Carboplatin AUC2 Q1W and Radiotherapy: 41,4 Gy in 23 fractions. Cohort C Chemotherapy Subjects with operable esophageal cancer eligible for neoadjuvant chemoradiotherapy will receive Nivolumab 240mg Q2W, concomitantly with RT Then surgery 4-12 weeks after RT. Within 6-12 months after surgery: Adjuvant Nivolumab 480mg Q4W, for 12 months. 6 patients in total. Neoadjuvant chemotherapy: Concomitantly Paclitaxel 50mg/m2 and Carboplatin AUC2 Q1W and Radiotherapy: 41,4 Gy in 23 fractions. Cohort A Nivolumab Subjects having palliative radiotherapy towards esophageal tumor will receive concomitant therapy With Nivolumab i.v. 240mg Q2W: first 6 patients, 360mg Q3W: Next 6 patients or 480mg Q4W: Last 6 patients, treatment to progression or up to 2 years of treatment. Radiotherapy: 2 Gy / day, (5 fx/week) to a total of 20 - 50 Gy in 25fx (2-4Gy/fx) at the decision of the responsible physician. Cohort B Nivolumab Subjects receiving definitive chemoradiotherapy for esophageal cancer will receive concomitant therapy with Nivolumab 240mg Q2W, during RT, and continued with 480mg Q4W, treatment to progression or up to 1 year after completion of radiotherapy. 6 patients in total. Chemotherapy: Paclitaxel i.v. 175mg/m2 and Carboplatin AUC5, then after 21 days Radiotherapy 1,8 Gy / day (5 fx/week) up to 50,4 Gy in 28fx and concomitantly Paclitaxel 50mg/m2 and Carboplatin AUC2 Q1W and Nivolumab as described above. Cohort C Nivolumab Subjects with operable esophageal cancer eligible for neoadjuvant chemoradiotherapy will receive Nivolumab 240mg Q2W, concomitantly with RT Then surgery 4-12 weeks after RT. Within 6-12 months after surgery: Adjuvant Nivolumab 480mg Q4W, for 12 months. 6 patients in total. Neoadjuvant chemotherapy: Concomitantly Paclitaxel 50mg/m2 and Carboplatin AUC2 Q1W and Radiotherapy: 41,4 Gy in 23 fractions.
- Primary Outcome Measures
Name Time Method Safety: The primary end point in this study is safety measurements done to determine the safety profile of the treatment; safety parameters included adverse events, biochemistry, hematology, vital signs and performance status. Adverse events are recorded according to CTCAE v5.0 (CTCAE grade 2-5 rate). Safety: The primary end point in this study is safety measurements done to determine the safety profile of the treatment; safety parameters included adverse events, biochemistry, hematology, vital signs and performance status. Adverse events are recorded according to CTCAE v5.0 (CTCAE grade 2-5 rate).
Feasibility: The feasibility of conducting the study will be reported as number of patients screened, and number of patients successfully included into the study per one year of accrual time. Feasibility: The feasibility of conducting the study will be reported as number of patients screened, and number of patients successfully included into the study per one year of accrual time.
- Secondary Outcome Measures
Name Time Method Overall Survival: The time from onset of treatment (day 1) to death from any cause. Overall Survival: The time from onset of treatment (day 1) to death from any cause.
Infield and Outfield Response to Treatment: The response rate as measured by RECIST 1.1 and immune-related RECIST (ir-RECIST) within the irradiated volume (infield) verses outside the irradiated volume (outfield). Infield and Outfield Response to Treatment: The response rate as measured by RECIST 1.1 and immune-related RECIST (ir-RECIST) within the irradiated volume (infield) verses outside the irradiated volume (outfield).
Progression Free Survival (Only Cohort B): The time from treatment start (day -21) until the disease progresses (PD) as determined by investigators from tumor assessments per RECIST or death from any cause. Progression Free Survival (Only Cohort B): The time from treatment start (day -21) until the disease progresses (PD) as determined by investigators from tumor assessments per RECIST or death from any cause.
Disease Free Survival (Only Cohort C): The time from surgery until recurrency or occurrence of disease progression as determined by investigators from tumor assessments per RECIST. Disease Free Survival (Only Cohort C): The time from surgery until recurrency or occurrence of disease progression as determined by investigators from tumor assessments per RECIST.
Pathology Complete Response Rate (Only Cohort C): The complete response rate in the surgical specimen by Chirieac grading by pathologist. Pathology Complete Response Rate (Only Cohort C): The complete response rate in the surgical specimen by Chirieac grading by pathologist.
Quality of Life:Quality of Life Questionnaires (QLQ) by patient reported outcomes EORTC QLQ-C30, EORTC QLQ-OG25 and EQ-5D. Quality of Life:Quality of Life Questionnaires (QLQ) by patient reported outcomes EORTC QLQ-C30, EORTC QLQ-OG25 and EQ-5D.
Trial Locations
- Locations (1)
Oslo University Hospital HF
🇳🇴Oslo, Norway
Oslo University Hospital HF🇳🇴Oslo, NorwayGeir Olav HjortlandSite contact23026600goo@ous-hf.no